Abstract
BackgroundEndothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs.MethodsUsing different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice.ResultsWe demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect.ConclusionsOur results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis.Da6HRv1cCSRgBNnKPBZEzuVideo . (MP4 46355 kb)
Highlights
Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites
We have demonstrated that these Endothelial Colony Forming Cells (ECFCs) give rise to higher number of colonies and can be extensively expanded in-vitro compared to ECFCs derived from adult peripheral blood (APB-ECFCs) and their initial clonogenic potential is predictive of their further properties [12]
We have recently demonstrated in a model of bio-artificial vessel that human Cord Blood (CB)-ECFCs implanted in a microfluidic chambers were able to suppress allogenic T cells in a dose dependent manner [32]
Summary
Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Little is known about immunological profile and function of TNFR2 in EPCs. Circulating Endothelial Progenitor Cells (EPCs) are nondifferentiated endothelial cells (ECs) first isolated from adult blood [1]. Circulating Endothelial Progenitor Cells (EPCs) are nondifferentiated endothelial cells (ECs) first isolated from adult blood [1] They are able to integrate vascular structures at damaged or neo-vascularization sites where they differentiate into mature ECs [2, 3], and are crucial for maintaining the vascular integrity [4, 5]. ECFCs are accepted as true EPCs progeny expressing EC markers, displaying features of stem/progenitor cells and having high clonogenicity and proliferation rate [10]. ECFCs still bear stem cell features and this could potentially influence their immunogenic properties
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